Since alcoholism is associated with decreased serotonin turnover, we have focused on genetic determinants of serotonergic behaviors to identify factors contributing to a predisposition to alcoholism. In the neurons of the raphe nuclei, serotonin biosynthesis is governed by the activity of the tryptophan hydroxylase (TPH) enzyme, which is rate-limiting. Sequences from the TPH promoter and upstream control regions have been combined with the coding sequence of the HSV thymidine kinase gene. This construct is being introduced into mouse embryos to create transgenic mice. Injection of ganciclovir into the brain of these transgenic mice should specifically ablate serotonergic neurons in the vacinity of the injection site. These studies will be used to investigate the role of serotonergic neurons in various behaviors, neural pathways and brain development.